KZN is the epicentre of the epidemic

Meningitis in the context of the

HIV epidemic14th March 2013

Kerrigan McCarthy MBBCh, DTM+H, FCPath (Micro)

KZN is the epicentre of the epidemic

Image courtesy Salome Charalambous

A note on our context…..

A note on our context….Meningitis and TB across the globe

It’s a killer…..

Meningitis - overview – A case study………..and all the things that go through our heads

? Any immediate actionDiagnostic proceduresAnti-infective chemotherapyPalliative and nursing careHIV diagnosis and managementPrognosis and long term sequelae…..An note on prevention

A presentation we are all too familiar with:Ms PN, brought in by boyfriend26 yrs old, resident with her

boyfriend in local township, unemployed mother of 2

History taking is difficult –but it appears thatM/C is headache & confusion, progressive

over 2 weeksOccasional cough, fever and nightsweats,

loss of weightNo previous illnessNo previous admissionsNot tested ever for HIV, apparently

A presentation we are all too familiar with: General examination:

Axillary temperature 37.5oC Resp rate 18/min Bp 90/60mmHg Pulse rate 110/min Generalised LNs, pale mucous membranes, diffuse

seborrheic dermatitis, oral thrush On examination of CNS

Mini-mental status exam GCS 14; poor recall, not orientated to time, person or

place ?neckstiffness Fundi not visualised No localising signs

Other organ systems Chest clear Cor – no abnormalities detected Abdomen – soft, non-tender

Going through our minds……

Sub-acute meningo-

encephalitis in a young person

with signs of HIV infection

Any immediate action required

before diagnostic tests can be

done?

Diagnostic procedures• LP• ?CT / MRI

Brain

Anti-infective chemotherapy• Empiric• specific

Palliative and nursing care•Pain relief•Hydration•Prevention of bed sores

HIV diagnosis and management•Disclosure to family?

Prognosis – • how aggressive

should I be?• Will State

Hospitals serve this patient well?

Long term sequelae•Financial implications

Going through our minds……

Sub-acute meningo-

encephalitis in a young person

with signs of HIV infection

Any immediate action

requiredbefore diagnostic tests can be done?

Diagnostic procedures• LP• ?CT / MRI

Brain

Anti-infective chemotherapy• Empiric• specific

Palliative and nursing care•Pain relief•Hydration•Prevention of bed sores

HIV diagnosis and management•Disclosure to family?

Prognosis – • how aggressive

should I be?• Will State

Hospitals serve this patient well?

Long term sequelae•Financial implications

Immediate action….If LP can’t be done immediately…

(E.g. patient at primary health clinic (PHC)/other venue and needs transfer or patient has localising signs and needs CT brain)

Antibacterials?

Antifungals?

Steroids?

Should we start ivi antibiotics?

Do serum cryptococcal antigen using LA or LFA; if positive, start on oral fluconazole 800mg until LP can be done

If bacterial or TB meningitis suspected – should we give steroids?

Going through our minds……

Sub-acute meningo-

encephalitis in a young person

with signs of HIV infection

Any immediate action

requiredbefore diagnostic tests can be done?

Diagnostic procedures• LP• ?CT / MRI

Brain

Anti-infective chemotherapy• Empiric• specific

Palliative and nursing care•Pain relief•Hydration•Prevention of bed sores

HIV diagnosis and management•Disclosure to family?

Prognosis – • how aggressive

should I be?• Will State

Hospitals serve this patient well?

Long term sequelae•Financial implications

LP and laboratory tests to facilitate diagnosis of cause of meningitisShould I do a lumbar

puncture?Is it safe?

Is there raised intra-cranial pressure? Are there localising signs? Is there gross impairment of

consciousness?

• Papilloedema is difficult to exclude in unco-operative patients

• ICP in persons with CM requires LP as part of mx

• VI cranial nerve palsy often associated with CM, requires LP

LP and laboratory tests to facilitate diagnosis of cause of meningitisShould I do a lumbar

puncture?Is it safe?

Is there raised intra-cranial pressure? Are there localising signs? Is there gross impairment of

consciousness?

Brouwer et al. Dilemmas in the diagnosis of meningitis. Lancet 2013:380:1684-92

LP and laboratory tests to facilitate diagnosis of cause of meningitisShould I do a

lumbar puncture?What if the CNS signs are

subtle, such as Very moderate neck stiffness Slight/occasional confusion

or subtle personality changes and/or memory loss

• ALWAYS DO LP if you have any reason to consider intra-cranial pathology

The differential diagnosis - working within the HIV epidemic

Could this be an acute/sub-acute bacterial meningitis?

Suggestive si/syAcute onsetMarked neck stiffnessNo antecedent history of

LOW etcHigh grade pyrexia on

examinationImage courtesy Anne von Gottberg, NICD

LP and laboratory tests to facilitate diagnosis of cause of meningitis

Aetiology Typical Cell count

Typical CSF chemistry

Microscopy and Culture

Specific tests

Bacterial PMNsLymphs

Protein Gram’s stain helpfulResult due 24-48 hrs

Bacterial latex agglutination

Fungal (cryptococcal)

PMNsLymphs

Protein India inkResult due 14 days

LA or Lateral flow assay (new)

Tuberculous PMNsLymphs

Protein ZN rarely positiveResult due 6 weeks; uncommonly positive

GeneXpert not more helpful than culture

Viral PMNsLymphs

Protein Not helpful routinely PCR

Commonly isolated organisms

Gram-positive diplococci – Streptococcus pneumoniaeGram-negative cocci – Neisseria meningitidisGram-negative cocco-bacilli – Haemophilus influenzaeGram-positive bacilli – Listeria monocytogenes

Uncommon: Gram-negative enteric bacterial – Salmonella speciesGram-negative non-fermenters – Pseudomonas species

A note on epidemiology

Cohen et al. AIDS AIDS 2010, 24:1351–1360

The differential diagnosis - working within the HIV epidemic

Could this be a cryptococcal meningitis / meningo-encephalitis

Suggestive si/syCD4<200 cells/mm3, but

often <50; Diplopia / 6th CN palsySubtle changes – memory

loss, mood changesSkin lesions

Cutaneous cryptococcal infection–

VI CN palsy

A note on epidemiologyCryptococcal meningitis across the globe

A note on epidemiologyCryptococcal meningitis across the globe

It’s a killer…..

LP and laboratory tests to facilitate diagnosis of cause of meningitis

Aetiology Typical Cell count

Typical CSF chemistry

Microscopy and Culture

Specific tests

Bacterial PMNsLymphs

Protein Gram’s stain helpfulResult due 24-48 hrs

Bacterial latex agglutination

Fungal (cryptococcal)

PMNsLymphs

Protein India inkResult due 14 days

LA or Lateral flow assay (new)

Tuberculous PMNsLymphs

Protein ZN rarely positiveResult due 6 weeks; uncommonly positive

GeneXpert not more helpful than culture

Viral PMNsLymphs

Protein Not helpful routinely PCR

A note on newer diagnosticsLateral flow assay for C neoformans in CSF

Simple and quick: Results available in 10 minutes

Accessible: can be done at the bedside

Effective: Highly sensitive and accurate (>95%)

Affordable: costs approximately 16 rand per test

Slide courtesy N Govender. NICD

The differential diagnosis - working within the HIV epidemicCould this be a

tuberculous meningitis?

Suggestive si/syChronicity with progressive

worsening of headache over weeks

Loss of weight, night sweatsFocus of TB infection

elsewhereLNs, lungs; disseminated infection with

pancytopenia

The differential diagnosis - working within the HIV epidemicTB meningitis

Definite –culture or ZN positive (47/109 cases)

ProbableClinical features of

meningitisSugestive CSF findings1 of the following

CXR consistent with PTB Extrameningeal TB (e.g. LNs or

splenic microabscesses on abd u/s)

CT brain evidence of TB such as basal meningeal enhancement, hydrocephalus or enhancementMarais et al. Presentation and outcome of TB meningitis in a high HIV prevalence setting. PLOS ONE

6(5):e20077)

LP and laboratory tests to facilitate diagnosis of cause of meningitis

Aetiology Typical Cell count

Typical CSF chemistry

Microscopy and Culture

Specific tests

Bacterial PMNsLymphs

Protein Gram’s stain helpfulResult due 24-48 hrs

Bacterial latex agglutination

Fungal (cryptococcal)

PMNsLymphs

Protein India inkResult due 14 days

LA or Lateral flow assay (new)

Tuberculous PMNsLymphs

Protein ZN rarely positiveResult due 6 weeks; uncommonly positive

GeneXpert not more helpful than culture

Viral PMNsLymphs

Protein Not helpful routinely PCR

A note on newer diagnosticsGeneXpert for M. tuberculosis in CSF

Not validated for non-sputum specimens

Limited use with CSF, Cultures are uncommonly positiveXpert sensitivity is 75% of culture

positive cases

The differential diagnosis - working within the HIV epidemic

Could this be a viral encephalitis?HSV, VZV, enterovirus

Suggestive si/syHigh red cell countFocal temporal lobe signsOccasionally oral HSV or

disseminated VZV skin rash

Large vessel involvement with haemorrhagic CVA

LP and laboratory tests to facilitate diagnosis of cause of meningitis

Aetiology Typical Cell count

Typical CSF chemistry

Microscopy and Culture

Specific tests

Bacterial PMNsLymphs

Protein Gram’s stain helpfulResult due 24-48 hrs

Bacterial latex agglutination

Fungal (cryptococcal)

PMNsLymphs

Protein India inkResult due 14 days

LA or Lateral flow assay (new)

Tuberculous PMNsLymphs

Protein ZN rarely positiveResult due 6 weeks; uncommonly positive

GeneXpert not more helpful than culture

Viral PMNsLymphs

Protein Not helpful routinely PCR

A note on epidemiology…. Common things occur commonly

Hospital Country Sample size

HIV infected

Bacterial/pyogenic

Tuberculosis

Crypto-coccal

Aseptic/viral

Mulago and Mbarana1

Uganda 416 90% 4% 8% 59% 29%

GF Jooste2 South Africa

1737 96% 19% 13% 30% 38%

Queen Elizabeth3

Malawi 263 77% 20% 17% 43% 20%

Harare4 Zimbabwe 200 90% 16% 12% 45% 28%

Average 2616 93% 9.3% 12.7% 37% 41%

Slide courtesy D Boulware, CROI 2013

Other uncommon causes of a lymphocytic meningitis…

Or perhaps syphilitic meningo-encephalitis due to Treponema pallidum?

Outliers in the differential of a sub-acute meningo-encephalitis

HIV dementia?Metabolic derangements? Intra-cranial bleed?Trauma?Space occupying lesions

TuberculomaCryptococcomaAbscessCNS lymphoma

Or is this merely sepsis with delirium?

The differential diagnosis – a summaryInfectious causes of meningo-

encephalitisBacterial causes

Streptococcus pneumoniae Haemophilus influenzae Listeria monocytogenes Gram-negative bacteria

Fungal causes Cryptococcus neoformans

Mycobacterial and treponemal causes Mycobacterium tuberculosisSyphilitic meningitis

Viral encephalitis Herpes simplex Herpes Zoster Enterovirus

Space-occupying lesionsToxoplasma gondii (and

other parasitic organisms)AbscessTuberculoma,

Cryptococcoma

Non-infectious causesHIV encephalopathyIntra-cranial bleedLymphoma (and other

neoplasms)Toxic, metabolic, auto-

immune, etc

Going through our minds……

Sub-acute meningo-encephalitis in a

young person with signs of HIV infection

Any immediate action requiredbefore

diagnostic tests can be done?

Diagnostic procedures• LP• ?CT / MRI

Brain

Anti-infective chemotherapy• Empiric• specific

Palliative and nursing care• Pain relief• Hydration• Prevention of

bed sores

HIV diagnosis and management• Disclosure to

family?

Prognosis – • how

aggressive should I be?

• Will State Hospitals serve this patient well?

Long term sequelae• Financial

implications

Anti-infective chemotherapyBacterial meningitis

Empiric treatment (following Gram’s stain)Ceftriaxone +/- vancomycin

Depends on local susceptibility profile of S. pneumoniaeConsider amoxicillin ivi if not using vancomycin (Listeria

is resistant to cephalosporins)Specific therapy

3rd generation cephalosporin adequate for GPC, GNB including Haemophilus influenzae

Ask for pneumococcal MICs to penicillin and ceftriaxoneAmoxicillin for Listeria

Anti-infective chemotherapyBacterial meningitis – empiric therapy

Van der Beek. Advances in the treatment of meningitis. Lancet 390: 1690. 2012

Anti-infective chemotherapyBacterial meningitis – empiric therapy

Alter based on Gram’s stain result

Anti-infective chemotherapySpecific therapy for S pneumoniae meningitis

Slide courtesy Anne von Gottberg, NICD

Anti-infective chemotherapy

Slide courtesy Anne von Gottberg, NICD

Anti-infective chemotherapy

Anti-infective chemotherapyAdjunctive steroids for bacterial meningitis

Studies are confusingIn adults, in high socio-economic countries,

dexamethasone improves outcome, reduces adverse effects, but not in low income countries

Children – definite benefit if given on or with the first dose of antibiotics

Dose of dexamethasoneKids – 0.6mg/kgAdults 10mg every 6 hrly

Van der Beek. Advances in the treatment of meningitis. Lancet 390: 1690. 2012

Anti-infective chemotherapyCryptococcal meningitis

New recommdendation – revised guidelines from HIV clinician’s society:

Anti-infective chemotherapyCryptococcal meningitis

Why not fluconazole alone?

Bicanic T, Meintjes G, et al Fungal burden, early fungicidal activity, and outcome in cryptococcal meningitis in antiretroviral-naive or antiretroviral-experienced patients treated with amphotericin B or fluconazole. Clin Infect Dis. 2007 Jul 1;45(1):76-80. Epub 2007 May 25.

Anti-infective chemotherapyCryptococcal meningitis

Why not fluconazole alone?

Bicanic T, Meintjes G, et al Fungal burden, early fungicidal activity, and outcome in cryptococcal meningitis in antiretroviral-naive or antiretroviral-experienced patients treated with amphotericin B or fluconazole. Clin Infect Dis. 2007 Jul 1;45(1):76-80. Epub 2007 May 25.

Anti-infective chemotherapyCryptococcal meningitis

Why AMB+ fluconazole?

AMB alone

AMB + fluconazole 800mg

Pappas PG, et al. Clin Infect Dis. 2009 Jun 15;48(12):1775-83.

Anti-infective chemotherapySupplementary

management for Cryptococcal meningitisManagement of raised

intracranial pressureEssential to mortalityMeasure pressure at

baselineTap if symptomatic

(worsening headache, LOC, 6th CN palsy)

Anti-infective chemotherapySupplementary

management for Cryptococcal meningitis:Prehydration and K+

supplementation to prevent renal decompensation/failure 2o to amphotericin B

Anti-infective chemotherapyTB meningitis

Practically this is a diagnosis of exclusionCSF cultures often negative for TBPrednisone essential

Brouwer et al. Dilemmas in the diagnosis of meningitis. Lancet 2013:380:1684-92

Going through our minds……

Sub-acute meningo-encephalitis in a

young person with signs of HIV infection

Any immediate action requiredbefore

diagnostic tests can be done?

Diagnostic procedures• LP• ?CT / MRI

Brain

Anti-infective chemotherapy• Empiric• specific

Palliative and nursing care• Pain relief• Hydration• Prevention of

bed sores

HIV diagnosis and management• Disclosure to

family?

Prognosis – • how

aggressive should I be?

• Will State Hospitals serve this patient well?

Long term sequelae• Financial

implications

Palliative and nursing carePain relief

WHO analgesic ladderHydration

Watch meticulously, and esp if giving AMB

Enlist family if nursing care sub-optimal

Prevention of bed soresCrucialEnlist family if nursing

care is suboptimal

Going through our minds……

Sub-acute meningo-encephalitis in a

young person with signs of HIV infection

Any immediate action requiredbefore

diagnostic tests can be done?

Diagnostic procedures• LP• ?CT / MRI

Brain

Anti-infective chemotherapy• Empiric• specific

Palliative and nursing care• Pain relief• Hydration• Prevention of

bed sores

HIV diagnosis and management• Disclosure to

family?

Prognosis – • how

aggressive should I be?

• Will State Hospitals serve this patient well?

Long term sequelae• Financial

implications

HIV diagnosis and management in patients with meningitis Often tricky to handle

when patient is confused and brought in by family

HIV diagnosis and management is ultimately lifesaving

Options:Wait and offer HIV test

when confusion abatesDiscuss with the family

and obtain consent to test while patient confused

HIV diagnosis and management in patients with meningitisTiming of ART is critical

Early ART improves prognosis in PTB – (STRIDE, SAPIT, CAMELIA studies) esp CD4 <50 cells/mm3,

BUT…..timing of ART initiation in pts with meningitis is complicated by potential for IRIS, and ICP47% of 34 patients with

TB meningitis developed TB IRIS

Image courtesy G MeintjiesMarais et al CID 2013:56 (3):450

HIV diagnosis and management in patients with meningitis

Boulware et al. ART Initiation within the First 2 Weeks of Cryptococcal Meningitis Is Associated with Higher Mortality: A Multisite Randomized Trial

CROI 2013 LB#144

HIV diagnosis and management in patients with meningitis

Boulware et al. ART Initiation within the First 2 Weeks of Cryptococcal Meningitis Is Associated with Higher Mortality: A Multisite Randomized Trial

CROI 2013 LB#144

ART >4 weeks after AMB start

ART 7-11 days after AMB start

HIV diagnosis and management in patients with meningitisImmune Reconstitution Inflammatory Syndrome

(IRIS)Recommendation:

For proven CC meningitis, ART should not be started until 4 weeks after amphotericin B initiation.

For TB meningitis – no evidence for timing of ART startFollow your intuition; do not initiate until symptoms of raised

intracranial pressure have abatedALWAYS use prednisone 1.5mg/kg for 2/52, followed by

0.75mg/kg for 2/52, then stop, do not wait for IRIS to occur

Be careful to use ART regimen that is compatible with TB treatment

Meintjies and Sonderup, CMEJ

Going through our minds……

Sub-acute meningo-encephalitis in a

young person with signs of HIV infection

Any immediate action requiredbefore

diagnostic tests can be done?

Diagnostic procedures• LP• ?CT / MRI

Brain

Anti-infective chemotherapy• Empiric• specific

Palliative and nursing care• Pain relief• Hydration• Prevention of

bed sores

HIV diagnosis and management• Disclosure to

family?

Prognosis – • how

aggressive should I be?

• Will State Hospitals serve this patient well?

Long term sequelae• Financial

implications

PrognosisTB meningitis

Marais et al. Presentation and outcome of TB meningitis in a high HIV prevalence setting. PLOS ONE 6(5):e20077)

PrognosisCryptococcal meningitis

Park et al. Int J STD and AIDS. 2011:22:199

Prevention is better than cureEarly HIV diagnosisVaccination when CD4 count high

Pneumococcal vaccinationEarly / appropriate ART initiationLow CD4 count

INH prophylaxisScreening for cryptococcal disease

ConclusionWe are in the

middle of a devastating epidemic….